Norbutrin 5, 10, 20 5 mg, 10 mg, 20 mg Transdermal Patch

NORBUTRIN is indicated for the treatment of chronic musculoskeletal pain of the joints and the lower back when that pain is of moderate to severe intensity sufficient to require an opioid to obtain adequate analgesia.

Posology
NORBUTRIN should be worn continuously for 7 days. Patients aged 18 years and over: The lowest NORBUTRIN dose available, NORBUTRIN 5 (5 u03bcg/h) should be used as the initial dose in all patients.
Titration
During initiation, titration, and treatment with NORBUTRIN, patients may continue their existing NSAID or paracetamol regimen as needed. The dose of NORBUTRIN should not be increased at less than 3-day intervals when steady state levels are attained. Changes in NORBUTRIN dosage may be individually titrated based on the need for supplemental analgesia and the patientu2019s analgesic response to NORBUTRIN.
To increase the dose, a larger patch should replace the patch that is currently being worn, or a combination of patches should be applied in different places to achieve the desired dose. It is recommended that no more than two patches be applied at the same time, regardless of patch strength. Titration should continue every 3 - 7 days until adequate analgesia is achieved. If adequate pain control cannot be achieved with NORBUTRIN, therapy with NORBUTRIN should be discontinued and the patient converted to an appropriate analgesic regimen as determined by a physician.
Special populations
Renal impairment: No special dose adjustment of buprenorphine is necessary in patients with renal impairment. Hepatic impairment: There is no need for dosage adjustment when using NORBUTRIN in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment may accumulate buprenorphine during NORBUTRIN treatment. NORBUTRIN should not be used in such patients (see section 4.3). Paediatric population: The safety and efficacy of NORBUTRIN in patients under 18 years of age has not been established.
Method of administration
In order to minimise the potential of skin reactions (see section 4.4) NORBUTRIN should be applied to non-irritated, intact skin of the upper outer arm, upper chest, upper back or the side of the chest. NORBUTRIN should be applied to a relatively hairless or nearly hairless skin site. If none are available, the hair at the site should be clipped, not shaven. Application sites should be rotated whenever a transdermal patch is replaced or added. Application sites should be re-used at no less than 3-week intervals. If the application site must be cleaned, it should be done with clear water only. Soaps, alcohol, oils, lotions, or abrasive devices should not be used. The skin must be dry before the transdermal patch is applied. NORBUTRIN should be pressed firmly in place at the application site, making sure contact is complete, especially around the edges. If the edges of the begin to peel off, the edges may be taped down with suitable skin tape. If a transdermal patch falls off, a new one should be applied. Bathing, showering, or swimming should not affect the system. While wearing NORBUTRIN, patients should be advised to avoid exposing the NORBUTRIN site to direct external heat sources such as heating pads, electric blankets, heat lamps, hot water bottles, etc., as an increase in absorption of buprenorphine may occur. The effects of the use of NORBUTRIN in hot tubs and saunas have not been studied.
Application directions
Open the pouch just before applying the patch. Take off the thin cover sheet. Attach the patch to the upper arm, upper chest, upper back, or sides of the chest. Press the patch with the hand for approximately 30 seconds and check that it is properly attached. The patch should not be used if the seal is broken. Discontinuation: After removal of NORBUTRIN, plasma concentrations decrease gradually. This should be considered when therapy with NORBUTRIN is to be followed by other opioids. As a general rule, a subsequent opioid should not be administered within 24 hours after removal of NORBUTRIN.

NORBUTRIN is contraindicated in:
u2022 patients with known hypersensitivity to buprenorphine or to any of the excipients;
u2022 patients suffering from delirium tremens;
u2022 patients with severe hepatic impairment;
u2022 patients suffering from myasthenia gravis;
u2022 opioid dependent patients and for narcotic withdrawal treatment;
u2022 conditions in which the respiratory centre and function are severely impaired or may become so;
u2022 patients who are receiving MAO inhibitors or have taken them within the last two weeks.
NORBUTRIN should not be used in patients with head injury, intracranial lesions or increased intracranial pressure, shock or a reduced level of consciousness of uncertain origin.

NORBUTRIN should not be used in patients with impaired respiratory function and in patients concurrently receiving monoamine oxidase inhibitors (MAOIs) or who have received MAOIs within the previous two weeks (see sections 4.3 and 4.5). NORBUTRIN should be used with particular caution in patients with acute alcohol intoxication, head injury, shock, a reduced level of consciousness of uncertain origin, intracranial lesions or increased intracranial pressure. NORBUTRIN is contraindicated in patients with severe hepatic impairment (see section 4.3). Severe febrile illness may increase the rate of buprenorphine absorption from NORBUTRIN. NORBUTRIN should be used with caution in patients with constipation. Caution should be exercised in patients suffering from sleep apnoea. NORBUTRIN may lower the seizure threshold in patients with a history of seizure disorder. Since CYP3A4 inhibitors may increase concentrations of buprenorphine (see Section 4.5), patients already treated with CYP3A4 inhibitors should have their dose of NORBUTRIN carefully titrated since a reduced dosage might be sufficient in these patients. NORBUTRIN is not recommended for analgesia in the immediate post-operative period or in other situations characterised by rapidly varying analgesic requirement.
Respiratory depression
Respiratory depression is the primary risk of opioid excess. Opioids may cause sleep-related breathing disorders including sleep-related hypoxemia and central sleep apnoea (CSA). CSA risk may be increased in a dose-dependent manner with opioid use in some patients. In patients who present with CSA, consider decreasing the total opioid dosage. Pre-existing sleep apnoea may be made worse with opioids (see section 4.8). In patients who present with CSA, consider decreasing the total opioid dosage.
CNS depressants co-administration
Concomitant use of sedative medicines such as benzodiazepines or related medicines and buprenorphine may result in sedation, coma, respiratory depression and death. Therefore, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. The lowest effective dose should be used if a decision is made to prescribe opioids concomitantly with sedative medicines. The duration of treatment should be as short as possible. It is unknown if such severity can be expected from transdermal formulation of buprenorphine. The patients should be followed closely for signs and symptoms of sedation and respiratory depression (see section 4.5).
Serotonin syndrome
Concomitant administration of buprenorphine and other serotonergic agents, such as selective serotonin re-uptake inhibitors (SSRIs), MAO inhibitors, tricyclic antidepressants or serotonin norepinephrine re-uptake inhibitors (SNRIs) may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5). Symptoms of serotonin syndrome may include neuromuscular abnormalities, mental-status changes, autonomic instability and/or gastrointestinal symptoms. A dose reduction or discontinuation of therapy should be considered if serotonin syndrome is suspected, depending on the severity of the symptoms.
Medicine dependence, tolerance and potential for abuse
Prolonged use of NORBUTRIN may lead to medicine dependence (addiction), even at therapeutic doses, for all patients. The risks are increased in individuals with mental health disorder (e.g., major depression) or current or past history of substance misuse disorder (including alcohol misuse). Monitoring and additional support may be necessary when prescribing for patients at risk of opioid misuse. A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained online, and past and present medical and psychiatric conditions. The risks of developing tolerance should be explained to the patient. The signs that the patient is developing tolerance is that they may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. Overuse or misuse may result in overdose and/or death. The clinical need for analgesic treatment should be regularly reviewed. Patients should be closely monitored for signs of misuse, abuse, or addiction. Significant respiratory depression has been associated with buprenorphine, particularly by the intravenous route. A number of deaths have occurred when addicts have intravenously abused buprenorphine, usually concomitantly with benzodiazepines. Additional overdose deaths due to benzodiazepines and ethanol in combination with buprenorphine have been reported (see section 4.5). Caution should be exercised when prescribing NORBUTRIN to patients known to have, or suspected to having, problems with drug or alcohol abuse or serious mental illness.
Medicine withdrawal syndrome
Medicine withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with NORBUTRIN. When therapy is no longer required, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months. If withdrawal syndrome occurs, it is generally mild. It begins after 2 days and may last up to 2 weeks. The opioid drug withdrawal syndrome is characterised by some or all of the following: lacrimation, rhinorrhoea, yawning, restlessness, perspiration, chills, mydriasis, myalgia and palpitations. Other symptoms may also develop including agitation, anxiety, hyperkinesia, insomnia, irritability, tremor, weakness, abdominal cramps, nausea, vomiting, diarrhoea, anorexia, increased blood pressure, increased respiratory rate or heart rate. If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

NORBUTRIN must not be used concomitantly with MAOIs or in patients who have received MAOIs within the previous two weeks (see sections 4.3 and 4.4). NORBUTRIN should be used with caution in patients who are concurrently taking other central nervous system (CNS) depressants or other medicines that may cause hypotension, respiratory depression, profound sedation or potentially result in coma and death. Such medicines include other opioid analgesics, sedatives or hypnotics, general anaesthetics, phenothiazines, alcohol, centrally acting anti-emetics and benzodiazepines. Buprenorphine should be used cautiously when co-administered with serotonergic medicinal products, such as SSRIs, SNRIs, MAOIs or tricyclic antidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4). Effect of other active substance on the pharmacokinetics of buprenorphine: Reduction in hepatic blood flow induced by some general anaesthetics (e.g., halothane) and other medicines may result in a decreased rate of hepatic elimination of the medicine buprenorphine. Buprenorphine as in NORBUTRIN is mainly metabolised by glucuronidation and to a lesser extent (about 30 %) by CYP3A4. Concomitant treatment with CYP3A4 inhibitors may lead to increased plasma concentrations with exaggerated efficacy of buprenorphine. Interaction with the CYP3A4 inhibitor ketoconazole will have no clinically relevant increases in mean maximum (Cmax) or total (AUC) buprenorphine exposure following NORBUTRIN with ketoconazole as compared to NORBUTRIN alone. The interaction between CYP3A4 enzyme inducers and buprenorphine has not been studied. Co-administration of buprenorphine and enzyme inducers (e.g., phenobarbital, carbamazepine, phenytoin and rifampin) may lead to increased clearance which might result in reduced efficacy.

Women of childbearing potential /Contraception in males and females
NORBUTRIN should not be used in women of childbearing potential who are not using effective contraception.
Pregnancy
NORBUTRIN should not be used during pregnancy. There are no or limited data available for the use of buprenorphine in pregnant woman. It has been shown, towards the end of pregnancy, high doses of buprenorphine may induce respiratory depression in the neonate, even after a brief period of administration. Prolonged use of NORBUTRIN during pregnancy, may result in neonatal withdrawal. Buprenorphine has been shown to cross the placenta in humans. Buprenorphine has been detected in newborn blood, urine and meconium and also in motheru2019s milk at low concentrations.
Breastfeeding
NORBUTRIN Transdermal Patch should not be used during lactation. As buprenorphine is excreted in human milk.
Fertility
No human data on the effect of buprenorphine on fertility are available.

NORBUTRIN Transdermal Patch may impair the ability to drive and use machines. This pertains particularly in the beginning of treatment and in conjunction with other centrally acting substances including alcohol, sedatives, tranquillisers and hypnotics. In cases where a stable dose is used, a general restriction is not necessary. For patients who experience and are affected by side effects such as dizziness drowsiness and or blurred vision during treatment initiation or titration to a higher dose should not drive or use machines, for at least 24 hours after the patch has been removed. NORBUTRIN Transdermal Patch can also impair cognitive function and can affect a patient's ability to drive safely.

The following side effects have been reported during the use of buprenorphine:
The table lists adverse reactions reported from 9 completed studies with buprenorphine. The reactions are listed as MeDRA preferred term by system organ class and absolute frequency. In general, included adverse events are those with a relation to medicine use, and excluded adverse events are minor events, those that are too imprecise to be meaningful, and events that may be commonly observed in the absence of medicine therapy.
Tabulated summary of adverse reactions
MedDRA system organ class Frequency Adverse reactions
Immune system disorders Less frequent Anaphylactic reaction, hypersensitivity reaction (including oropharyngeal swelling and swollen tongue). Metabolism and nutrition disorders Frequent Anorexia Less frequent Dehydration * Psychiatric disorders Frequent Confusion, depression* , insomnia, nervousness , anxiety. Less frequent Affect lability, aggression, agitation, depersonalisation, euphoric mood, hallucinations, libido decreased, nightmares, psychotic disorder, restlessness, sleep disorder, medicine dependence. Nervous system disorders Frequent Dizziness, headache*, paraesthesia, somnolence, tremor. Less frequent Balance disorder, concentration impairment, coordination abnormal, dysarthria, dysgeusia, hypoaesthesia, involuntary muscle contractions, memory impairment, migraine, paraesthesia, sedation, seizures, speech disorder, syncope * , tremor , convulsions, hyperalgesia, sleep apnoea syndrome. Eye disorders Less frequent Dry eye, eyelid oedema, miosis, vision blurred, visual disturbance. Ear and labyrinth disorders Less frequent Ear pain, tinnitus, vertigo. Cardiac disorders Less frequent Angina pectoris, palpitations, tachycardia. Vascular disorders Frequent Vasodilatation. Less frequent Flushing, hypertension * , hypotension, orthostatic hypotension. Respiratory, thoracic and mediastinal disorders Frequent Dyspnoea * . Less frequent Asthma aggravated * , cough, hiccups, hyperventilation, hypoxia, respiratory depression, respiratory failure, rhinitis, wheezing. Gastrointestinal disorders Frequent Abdominal pain*, constipation*, diarrhoea, dry mouth, dyspepsia *, nausea* , vomiting * . Less frequent Diverticulitis * , dysphagia, flatulence, ileus. Hepato-biliary disorders Less frequent Biliary colic * . Skin and subcutaneous tissue disorders Frequent Erythema, exanthema, pruritus*, rash*, sweating* . Less frequent Contact dermatitis, dry skin, face oedema, pustules, uritcaria . Musculoskeletal and connective tissue disorders Frequent Muscular weakness. Less frequent Muscle cramp, muscle spasm, myalgia. Renal and urinary disorders Less frequent Urinary incontinence, urinary hesitation, urinary retention. Reproductive system and breast disorders Less frequent Erectile dysfunction, sexual dysfunction. General disorders and administration site conditions Frequent Application site reaction u2020 (including application site erythema, application site oedema, application site pruritus, application site rash) asthenia (including muscle weakness), chest pain, pain, peripheral oedema, tiredness. Less frequent Application site dermatitis**, chest pain, fatigue, influenza like illness, malaise, oedema, pyrexia *, rigors* , drug withdrawal syndrome. Investigations Less frequent Alanine amino-transferase increased, weight decreased. Injury, poisoning and procedural complications Less frequent Accidental injury (including fall). * At least one serious case u2020Includes: application site erythema, application site oedema, application site pruritus, application site rash. **In some cases, late onset local allergic reactions occurred with marked signs of inflammation. In such cases treatment with NORBUTRIN should be terminated. Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

The manifestations of NORBUTRIN overdose is an extension of its pharmacological actions. Respiratory depression has been absent in some cases of buprenorphine overdose. Respiratory depression including apnoea may occur in other overdose situations. Additional symptoms include sedation, drowsiness, nausea, vomiting, cardiovascular collapse and marked miosis. Remove any NORBUTRIN in contact with the patientu2019s skin and dispose of it properly. Establish and maintain a clear airway, assist and control respiration as indicated, and maintain adequate body temperature and fluid balance. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. A specific opioid antagonist such as naloxone may reverse the effects of buprenorphine, although naloxone may be less effective in reversing the effects of buprenorphine than other u03bc-opioid agonists. Treatment with continuous intravenous naloxone should begin with the usual doses but high doses may be required. Maintenance of adequate ventilation is essential when managing a NORBUTRIN overdose and more important than specific antidote treatment with a narcotic antagonist such as naloxone.